The conditions for maximal penetration of blood-borne proteins into the brain, from non-neural grafts to the brain, have been examined. Autografts of skeletal (nuchal) muscle and skin were placed on the pial surface (S) of medulla and cerebellum or into the parenchyma (P) of adult rats. S grafts consistently became innervated by, presumably, collateral sprouts from cranial nerves and survived for at least 1 year. P grafts did not become innervated and survived for no more than 6 months. Endogenous IgG (MW 160,000), detected immunohistochemically, entered the brain around the grafts for a very limited distance compared with blood-borne horseradish peroxidase (HRP) (MW 40,000). The furthest penetration into the brain of HRP was greater from S grafts (4.6mm) than from P grafts (2.2mm). S grafts that were only 0.5mm longer and wider than other grafts permitted significantly greater penetration (1.6 vs 0.9mm). Thus, large, pial grafts are the most effective ones to bring blood-borne macromolecules, normally excluded by the blood-brain barrier (BBB), into the brain. Receptor mediated vs bulk phase, endocytosis is being followed to learn how cerebral endothelium may selectively transport large molecules across the BBB. Like endothelium from other organs, brain endothelial cells in vitro avidly endocytose fluorochrome-tagged, acetylated, low density lipoprotein (AcLDL). This "scavenger," bulk uptake results in a pronounced labeling, seen with fluorescence microscopy, of endothelial lysosomes at 3 to 4 hours, via numerous, endocytosing pits and vacuoles, visualized by electron microscopy, with wheat germ agglutinin (WGA) lectin-HRP. A few large, coated pits and adjacent segments of cell membrane, some small vesicles, and a few tubules become heavily labeled with peanut and asparagus lectins. The sugar residues thus labeled are much more restricted on the cell surface than those bound to WGA lectin and may be related to receptor mediated endocytosis.